As antibiotics of the anthracycline type are known daunomycin which is also named daunorubicin in the specification of U.S. Pat. No. 3,616,242, as well as adriamycin which is also named doxorubicin in the specification of U.S. Pat. No. 3,590,028. These compounds have broad anticancer spectra against experimental tumors and have widely been utilized for clinical purposes as a chemotherapeutic anticancer agent.
While, daunomycin and adriamycin can exhibit a somewhat strong anticancer or antitumor activity against various kinds of cancers or tumors, but are not necessarily satisfactory as the anticancer agent or antitumor agent. That is, daunomycin and adriamycin have been utilized widely as a chemotherapeutic anticancer agent for clinical treatment of cancer-bearing patients, but they are also known to bring about serious side-effects such as leukocytopenia, alopecia, myocardiopathy and others, in many instances.
Therefore, it has hitherto been attempted to produce newly a variety of novel daunomycin-related compounds with the intention of providing such novel daunomycin-related compounds which would have a much enhanced anticancer or antitumor activity but with exhibiting a low toxicity. As some outcome of the attempts hitherto made, there have been proposed several compounds, for example, those known as aclacinomycins A and B; 4'-O-tetrahydropyranyl-adriamycin; N-monobenzyl- or N-dibenzyl-adriamycin.
Besides, U.S. Pat. No. 4,427,664 specification discloses 7-O-(3,4-di-O-acetyl-2,6-dideoxy-2-iodo-.alpha.-L-manno-hexopyranosyl)daun omycinone and 7-O- (3,4-di-O-acetyl-2,6-dideoxy-2-iodo-.alpha.-L-talo-hexopyranosyl)daunomyci none.
We, the present inventors, proceeded with our investigations in an attempt to provide novel derivatives of daunomycin and adriamycin which will exhibit a higher anticancer or antitumor activity than those of daunomycin or adriamycin but with a low toxicity. As a part of our investigations, we have already synthesized some derivatives of daunomycin and adriamycin in which the sugar moiety of daunomycin and adriamycin has been chemically modified. For example, the present inventors already reported 4'-O-tetrahydropyranyl-daunomycin or -adriamycin as well as 3'-deamino-3'-morpholino-daunomycin or -adriamycin.
Further, the present inventors succeeded in synthesizing such anthracycline derivatives having antitumor activities which are represented by the following general formula (A) ##STR2##
wherein R.sup.a stands for a hydrogen atom or a hydroxyl group, that is, 7-O-(2,6-dideoxy-2-fluoro-.alpha.-L-talopyranosyl)-daunomycinone and 7-O-(2,6-dideoxy-2-fluoro-.alpha.-L-talopyranosyl)-adriamycinone, which possess an anticancer or antitumor activity (see Japanese Patent Publication "Kokoku" Hei 6-31298 and European Patent No. 0230013).
The present inventors also succeeded in synthesizing such anthracycline derivatives having antitumor activities which are represented by the following general formula (B) ##STR3##
wherein R' stands for a group --(CH.sub.2).sub.m --H where m is an integer of 1.about.6,or R' stands for a group --(CH.sub.2).sub.n --COOH where n is an integer of 1.about.10 (see Japanese Patent Publication "Kokoku" Hei 7-42304 and European Patent No. 0275431).
The present inventors further succeeded in synthesizing such anthracycline derivatives having antitumor activities which are represented by the following general formula (C) ##STR4##
wherein R.sup.1 is a hydrogen atom or a hydroxyl group, R.sup.2 is a methoxy group or a hydrogen atom, and A and B each stand for a hydrogen atom or A and B as taken together form a chain of formula --CH.sub.2 --CH.sub.2 --O--CH.sub.2 --CH.sub.2 -- (see Japanese Patent Application First Publication "Kokai" Sho-64-203397). As examples of the anthracycline derivatives of the general formula (C), there may be mentioned 7-O-(3-amino-2,3,6-trideoxy-2-fluoro-.alpha.-L-talopyranosyl)daunomycinone ; 7-O-(3-amino-2,3,6-trideoxy-2-fluoro-.alpha.-L-talopyranosyl)adriamycinone ; 7-O-(2,3,6-trideoxy-2-fluoro-3-morpholino-.alpha.-L-talopyranosyl)adriamyc inone and others.
7-O-(2,6-Dideoxy-2-fluoro-.alpha.-L-talopyranosyl)adriamycinone, as one of the anthracycline derivatives of the general formula (A) given above, exhibits a remarkable antitumor activity, but is barely soluble in water, so that it had a difficulty in formulating into injection preparations. Then, the anthracycline derivatives of general formulae (B) and (C) above have been synthesized in an attempt to give such anthracycline derivatives which have an improved solubility in water. Amongst the derivatives of the general formula (C), 7-O-(3-amino-2,3,6-trideoxy-2-fluoro-.alpha.-L-talopyranosyl)adriamycinone is soluble in water, but the antitumor activity thereof has not been recognized to be remarkably higher than that of adriamycine, even though the former has the antitumor activity a little higher than that of the latter.
The present inventors further have continued our investigations in various ways with the intention of producing such novel anthracycline derivatives which can exhibit higher anticancer or antitumor activities than those of daunomycin, adriamycin and the antitumor anthracycline derivatives of the general formulae (A), (B) and (C) above, even at a low dosage, and which are of satisfactory solubility in water and of low toxicity.
The anticancer or antitumor activities of the anthracycline derivatives of the general formulae (A) and (B) above are, in fact, noticeably superior to those of daunomycin and adriamycin, but are not yet satisfactorily high enough. All of the anthracycline derivatives of the general formula (C) above are soluble in water, but most of those derivatives exhibit only an anticancer or antitumor activity substantially as high as or lower than that of adriamycin.
Therefore, there still exists a desire for providing such novel anthracycline derivatives which can exhibit higher anticancer or antitumor activities than those of the known anthracycline derivatives. Further, in general, it is always convenient for clinical applications to administer the anticancer or antitumor compounds in the form of injectable preparations. Thus, for the purpose of therapeutic treatments of a variety of cancers and tumors, a demand always exists in the art to provide and explore such novel anticancer or antitumor agents having a nature that they can exhibit a strong anticancer or antitumor activity but with low toxicity and also they are highly soluble in water.
In order to solve the problems above-mentioned, the present inventors have proceeded with our further investigations in an attempt to synthesize novel anthracycline derivatives having a new fluorinated amino-sugar moiety.
As a result of these further investigations, we have now succeeded in synthesizing 1-O-acetyl derivative of 4-amino-2,4,6-trideoxy-2-fluoro-.alpha.-L-mannopyranose and 4-amino-2,4,6-trideoxy-2-fluoro-.alpha.-L-mannopyranosyl bromide or their 3,4-di-O,N-protected derivatives as new compounds through a multi-step method with starting from methyl 4-O-benzyl-2,6-dideoxy-2-fluoro-.alpha.-L-talopyranoside which has been obtained in the synthesis of the anthracycline derivative of the general formula (A) shown hereinbefore (see the specification of Japanese patent application No. Hei-7-179621 filed Jun. 23, 1995 which is corresponding to PCT application No. PCT/JP96/01697 filed Jun. 19, 1996, now published under International publication No. WO 97/00880).
Then, by utilizing these 4-amino-2,4,6-trideoxy-2-fluoro-.alpha.-L-mannopyranose derivatives as synthesized for the first time and by taking such a method which comprises condensing the 4-amino-2,4,6-trideoxy-2-fluoro-.alpha.-L-mannopyranosyl group with the 7-hydroxyl group of daunomycinone or adriamycinone, we have earlier succeeded in synthesizing such novel daunomycinone derivative and adriamycinone derivative which are represented by the following general formula (D) ##STR5##
wherein R is a hydrogen atom or a hydroxyl group or an acid addition salt thereof, as such anthracycline derivatives which bear as the sugar moiety a 4-amino-2,4,6-trideoxy-2-fluoro-.alpha.-L-mannopyranosyl group where the amino group at the 4-position of this sugar moiety is of the equatorial direction. Furthermore, we have found that the novel anthracycline derivatives of the general formula (D) above are soluble in water, that they exhibit a high anticancer or antitumor activity even when they are administered to test animals at low dosages, and that development of acute toxicity does not take place in the test animals having received the administration of the anthracycline derivative of the formula (D) at the low dosages which can give high anticancer or antitumor effects in the test animals so treated (see the aforesaid Japanese patent application No. Hei-7-179621).
The daunomycinone or adriamycinone derivative of the general formula (D) contains the equatorically directed amino group at the 4-position of the sugar moiety thereof, and particular examples thereof include Compound (a) and Compound (b) of the following formulae (D-a) and (D-b), respectively.
(1) Compound (a): 7-O-(4-amino-2,4,6-trideoxy-2-fluoro-.alpha.-L-mannopyranosyl)daunomycinon e of the following formula ##STR6##
(2) Compound (b): 7-O-(4-amino-2,4,6-trideoxy-2-fluoro-.alpha.-L-mannopyranosyl)adriamycinon e of the following formula ##STR7##
It has been confirmed through "in vivo" tests that, among the anthracycline derivatives of the general formula (D) above, 7-O-(4-amino-2,4,6-trideoxy-2-fluoro-.alpha.-L-mannopyranosyl)adriamycinon e of the formula (D-b) exhibits a remarkably high antitumor activity against experimental tumors in animals and has a remarkably improved antitumor activity against mouse Leukemia L-1210 cell over adriamycin even when the compound of the formula (D-b) is administered at low dosages. While, it has also been found that althoguh the compound of the formula (D-b) is soluble in water and exhibits the above-mentioned excellent antitumor activity against mouse Leukemia L-1210 cell, this compound as tested in "in vitro" tests remains to exhibit against various human cancer cells such anticancer activities which are substantially as high as those of adriamycin.
Accordingly, one of the objects of this invention is to provide and explore new anticancer anthracycline derivatives having such properties that they can exhibit an excellent anticancer or antitumor activity and especially exhibit a stronger anticancer activity against various human cancer cells than adriamycin but they have a low toxicity and a high solubility in water.